System wide cofactor turnovers can propagate metabolic stability between pathways

Metabolic homeostasis, or low-level metabolic steady state, has long been taken for granted in metabolic engineering, and research priority has always been given to understand metabolic flux control and regulation of the reaction network. In the past, this has not caused concerns because the metabolic networks studied were invariably associated with living cells. Nowadays, there are needs to reconstruct metabolic networks, and so metabolic homeostasis cannot be taken for granted. For metabolic steady state, enzyme feedback control has been known to explain why metabolites in metabolic pathways can avoid accumulation. However, we reasoned that there are further contributing mechanisms. As a new methodology developed, we separated cofactor intermediates (CIs) from non-cofactor intermediates, and identified an appropriate type of open systems for operating putative reaction topologies. Furthermore, we elaborated the criteria to tell if a multi-enzyme over-all reaction path is of in vivo nature or not at the metabolic level. As new findings, we discovered that there are interactions between the enzyme feedback inhibition and the CI turnover, and such interactions may well lead to metabolic homeostasis, an emergent property of the system. To conclude, this work offers a new perspective for understanding the role of CIs and the presence of metabolic homeostasis in the living cell. In perspective, this work might provide clues for constructing non-natural metabolic networks using multi-enzyme reactions or by degenerating metabolic reaction networks from the living cell. Keywords: Metabolic stability, Metabolic steady state, Cofactor balance, Cofactor turnover, Enzyme feedback control, Emergent property of metabolic networ

Querying Social Practices in Hospital Context

Understanding the social contexts in which actions and interactions take place is of utmost importance for planning one’s goals and activities. People use social practices as means to make sense of their environment, assessing how that context relates to past, common experiences, culture and capabilities. Social practices can therefore simplify deliberation and planning in complex contexts. In the context of patient-centered planning, hospitals seek means to ensure that patients and their families are at the center of decisions and planning of the healthcare processes. This requires on one hand that patients are aware of the practices being in place at the hospital and on the other hand that hospitals have the means to evaluate and adapt current practices to the needs of the patients. In this paper we apply a framework for formalizing social practices of an organization to an emergency department that carries out patient-centered planning. We indicate how such a formalization can be used to answer operational queries about the expected outcome of operational actions.</p

Clustering of adverse health and educational outcomes in adolescence following early childhood disadvantage: population-based retrospective UK cohort study

Background: Disadvantage in early childhood (ages 0–5 years) is associated with worse health and educational outcomes in adolescence. Evidence on the clustering of these adverse outcomes by household income is scarce in the generation of adolescents born since the turn of the millennium. We aimed to describe the association between household income in early childhood and physical health, psychological distress, smoking behaviour, obesity, and educational outcomes at age 17 years, including the patterning and clustering of these five outcomes by income quintiles. Methods: In this population-based, retrospective cohort study, we used data from the Millennium Cohort Study in which individuals born in the UK between Sept 1, 2000, and Jan 1, 2002, were followed up. We collected data on five adverse health and social outcomes in adolescents aged 17 years known to limit life chances: psychological distress, self-assessed ill health, smoking, obesity, and poor educational achievement. We compared how single and multiple outcomes were distributed across early childhood quintile groups of income, as an indicator of disadvantage, and modelled the potential effect of three income-shifting scenarios in early childhood for reducing adverse outcomes in adolescence. Findings: We included 15 245 adolescents aged 17 years, 7788 (51·1%) of whom were male and 7457 (48·9%) of whom were female. Adolescents in the lowest income quintile group in childhood were 12·7 (95% CI 6·4–25·1) times more likely than those in the highest quintile group to have four or five adverse adolescent outcomes, with poor educational achievement (risk ratio [RR] 4·6, 95% CI 4·2–5·0) and smoking (3·6, 3·0–4·2), showing the largest single risk ratios. Shifting up to the second lowest, middle, and highest income groups would reduce multiple adolescent adversities by 4·9% (95% CI –23·8 to 33·6), 32·3% (–2·7 to 67·3), and 83·9% (47·2 to 120·7), respectively. Adjusting for parental education and single parent status moderately attenuated these estimates. Interpretation: Early childhood disadvantage is more strongly correlated with multiple adolescent adversities than any of the five single adverse outcomes. However, shifting children from the lowest income quintile group to the next lowest group is ineffective. Tackling multiple adolescent adversities requires managing early childhood disadvantage across the social gradient, with income redistribution as a central element of coordinated cross-sectoral action. Funding: UK Prevention Research Partnership

Clustering of adverse health and educational outcomes in adolescence following early childhood disadvantage: population-based retrospective UK cohort study

BACKGROUND: Disadvantage in early childhood (ages 0-5 years) is associated with worse health and educational outcomes in adolescence. Evidence on the clustering of these adverse outcomes by household income is scarce in the generation of adolescents born since the turn of the millennium. We aimed to describe the association between household income in early childhood and physical health, psychological distress, smoking behaviour, obesity, and educational outcomes at age 17 years, including the patterning and clustering of these five outcomes by income quintiles. METHODS: In this population-based, retrospective cohort study, we used data from the Millennium Cohort Study in which individuals born in the UK between Sept 1, 2000, and Jan 1, 2002, were followed up. We collected data on five adverse health and social outcomes in adolescents aged 17 years known to limit life chances: psychological distress, self-assessed ill health, smoking, obesity, and poor educational achievement. We compared how single and multiple outcomes were distributed across early childhood quintile groups of income, as an indicator of disadvantage, and modelled the potential effect of three income-shifting scenarios in early childhood for reducing adverse outcomes in adolescence. FINDINGS: We included 15 245 adolescents aged 17 years, 7788 (51·1%) of whom were male and 7457 (48·9%) of whom were female. Adolescents in the lowest income quintile group in childhood were 12·7 (95% CI 6·4-25·1) times more likely than those in the highest quintile group to have four or five adverse adolescent outcomes, with poor educational achievement (risk ratio [RR] 4·6, 95% CI 4·2-5·0) and smoking (3·6, 3·0-4·2), showing the largest single risk ratios. Shifting up to the second lowest, middle, and highest income groups would reduce multiple adolescent adversities by 4·9% (95% CI -23·8 to 33·6), 32·3% (-2·7 to 67·3), and 83·9% (47·2 to 120·7), respectively. Adjusting for parental education and single parent status moderately attenuated these estimates. INTERPRETATION: Early childhood disadvantage is more strongly correlated with multiple adolescent adversities than any of the five single adverse outcomes. However, shifting children from the lowest income quintile group to the next lowest group is ineffective. Tackling multiple adolescent adversities requires managing early childhood disadvantage across the social gradient, with income redistribution as a central element of coordinated cross-sectoral action

Longitudinal association of conduct and emotional problems with school exclusion and truancy: A fixed effect analysis of the UK Millennium Cohort Study

BACKGROUND: There is a need for causally stronger research on the association between child mental health and school exclusion and truancy. This study examines school exclusion and truancy in relation to both conduct and emotional problems and considers these problems both as predictors and as outcomes of school exclusion and truancy. METHOD: The sample included 15,236 individuals from the Millennium Cohort Study, a UK longitudinal birth cohort study. Conduct and emotional problems were assessed from childhood to adolescence (age 7, 11, 14 and 17 years), and reports of school exclusion and truancy were collected at age 11 and 14. Fixed effect analyses were used. RESULTS: Increases in conduct problems and emotional symptoms were associated with subsequent exclusion (OR 1.22, [95% CI 1.08-1.37] and OR 1.16, [1.05-1.29], respectively). Emotional symptoms, but not conduct problems, predicted truancy (OR 1.17, [1.07-1.29]). These estimates were similar for males and females. Exclusion was associated with an increase in conduct problems at age 14 (0.50, [0.30-0.69]), and for males, it was associated with an increase in emotional symptoms both at age 14 (0.39, [0.12-0.65]) and 17 (0.43, [0.14-0.72]). Truancy was associated with an increase in conduct problems at age 14 (0.41, [0.28-0.55]), and for females also at age 17 (0.22, [0.03-0.42]), and it was associated with increased emotional symptoms at age 14 (0.43, [0.25-0.62]) and 17 (0.44, [0.21-0.66]), which was similar for males and females. CONCLUSION: Results indicate a bidirectional association between emotional symptoms and school exclusion and truancy, as an increase in these symptoms was associated with later truancy and exclusion, and emotional symptoms increased following both school events. For conduct problems, the association was bidirectional for school exclusion, but unidirectional for truancy as these symptoms did not lead to truancy, but an increase in conduct problems was observed after both exclusion and truancy